Copper is an essential nutrient for all organisms. It is critical for connective tissue formation, angiogenesis, immune function, mitochondrial respiration, and neurological function. This requirement for copper is illustrated by Menkes disease, a genetic disorder of copper metabolism. Menkes disease is characterized by an overall copper deficiency and is caused by mutations in the Menkes protein (ATP7A). The ATP7A protein is a copper transporter belonging to the P-type ATPase family, and is required for the export of copper from cells. This function controls copper levels in most tissues of the body except the liver, where ATP7A is not expressed. The homeostasis of copper is altered by certain physiological conditions or pathologies. An example of the latter is Alzheimer[unreadable]s disease, the most common form of dementia affecting an estimated 5 million Americans. Alzheimer's disease is caused by the overproduction and deposition of aggregated amyloid-beta (A[unreadable]) protein as amyloid (senile) plaques within the brain. This process is associated with localized oxidative stress and neuronal loss, caused in part by inflammatory microglial cells. A[unreadable] is known to bind copper in postmortem brain of patients with Alzheimer's disease and copper concentrations are specifically elevated within the amyloid plaques in brains of Alzheimer's disease patients and animal models. The interaction between A[unreadable] and copper mediates the aggregation of the A[unreadable] peptide and promotes neuronal killing. These findings point to a role for copper in Alzheimer's disease pathogenesis. In contrast, however, studies in mice show that copper enrichment in the central nervous system reduces production of A[unreadable] and the frequency of amyloid plaques. It is the long-term goal of this research to understand at the molecular level how copper homeostasis contributes to Alzheimer's disease. To achieve this goal, we will characterize protective or pathogenic roles of copper in Alzheimer's disease using cell culture paradigms and mouse models of both Alzheimer's disease and defective copper homeostasis. Specific aims of the proposal include investigations into protective and detrimental roles of copper in Alzheimer's disease using cellular and biochemical approaches, and to evaluate these in the context of a transgenic mouse model of Alzheimer's disease. This research will shed light on the importance of copper in the pathogenesis of Alzheimer's disease, and whether the availability of this nutrient should be investigated in therapeutic strategies.